Vascular disease ultimately comprises the dominant killer and source of disability of men and women in the developed world.
Management of patients with advanced Coronary Artery Disease (CAD) in particular is a major challenge for the cardiologist and cardiac surgeon. Patients with advanced CAD frequently have limited symptoms with recurrent angina, angina at low work thresholds, breathlessness, and other debilitating conditions. These patients have often been through several “re-do” coronary bypass procedures and multiple percutaneous coronary interventions. Surgical and interventional options for these patients typically have been exhausted or will result in only partial revascularization. Therefore, therapy remains limited to the use of multiple anti-anginal medications, reduced activity, exertion, and stress level, and significant alteration and limitation of lifestyle.
The burgeoning field of therapeutic angiogenesis offers hope for these patients. The goal of this emerging approach is to therapeutically induce the growth and development of new vasculature in zones of severe ischemia in the myocardium, with the hope that new capillaries and arterioles generated will connect to remnant existing vasculature. These neo-vessels are viewed to act as collaterals, perfusing ischemic territories unapproachable by macro procedures such as angioplasty and bypass surgery.
Angiogenesis is a natural phenomenon, as narrowed arteries resulting in ischemia are known to promote (in some patients, to varying degrees) new arterial growth as an adaptive response—such that new arterial growth (including the development of pre-existing collateral vessels) is developed to circumvent the narrowings. The presence of such new arterial growth can limit symptomlogy and the size of a heart attack, or similarly in cases of cerebral ischemia, limit the infarct size and degree of damage caused by a stroke.
Several strategies are being pursued for therapeutic angiogenesis. Local injection of naked DNA or viral vectors coding for various angiogenic growth factors (eg, Vascular Endothelial-Derived Growth Factor (VEGF) and Fibroblast-derived Growth Factor (FGF) have been examined in animals and humans, as have local injections of actual growth factor proteins such as VEGF, FGF, and IGF. In addition, local delivery of endothelial cells and bone marrow-derived precursor stem cells are being studied. The corporation CARDIUM is currently evaluating an intra-coronary delivered pharmaceutical (Generx) for stimulation of coronary angiogenesis.
Intra-arterial injections of growth factors and other angiogeneic agents require an invasive catheterization procedure, which require a skilled operator with substantial infrastructure, and caries great cost to health care and substantial risks for the patient.
Another strategy that has recently been getting some attention is mechanically induced angiogenesis, as it has been scientifically shown in vitro and in-vivo that mechanical sheer stresses caused by hemodynamic forces, leads to endothelial liberation of beneficial mediators such as eNOS, VEGF and PCNA, and a large host of other beneficial mediators all known for stimulating angiogenesis.
In keeping with the above principles, non-invasive acoustic and mechanical delivery systems to the human body have been forwarded to assist angiogenesis, and in particular coronary angiogenesis.
Horzewski et al in U.S. Pat. No. 7,229,423 describes a piezoelectric actuator operable in the audible frequency ranges which delivers acoustic energy to the chest wall of a patient to cause increased uptake of angiogenic agents. The device offers very low micro-amplitude oscillations (considerably less than 0.1 mm) which cannot be felt by the patient, hence offering a limited therapeutic response to the target vessels. Similarly, many other piezoelectric actuators, mostly operable in the higher frequency ultrasonic ranges, have been proposed for use in causing angiogenesis, all of which provide limited penetrability to a targeted vasculature.
Kamm et al in US patent application 2003/00009119 A1 describes the use of external counter-pulsation techniques applied to the limbs or lower abdomen of a patient, to cause angiogenesis in the heart. The remote counter pulsation and use of periodic, gradual inflation and deflation of a pressure cuff, which increases the diastolic coronary blood flow velocity (and thus enhances coronary endothelial shear stresses) again offers a very limited, and almost insignificant agitative force/sheer forces which actually reach the coronaries.
Sackner in US patent application 20020103454 discloses a whole body “reciprocating movement platform” or bed which oscillates in a rhythmic to and fro motion (i.e. in the head to foot direction), delivering “external pulses” to a human body in the frequency range of 0.25-6 Hz, for a plurality of applications including stimulating angiogenesis. The 454 patent application invokes hemodynamic forces or “pulses” by virtue of the accelerations and deceleration's of the movement platform which purportedly instill sheer stresses from blood to endothelium of the vasculature; which is known to invoke the liberation of endogenous “beneficial mediators” such as t-PA, EDRF, and Nitric Oxide (all of which are of assistance in the improvement of blood flow and prophylaxis to disease). Again, the amount of forces which actually reach the target vasculature (such as the coronary arteries) are minimal as the oscillations are not of high intensity (i.e. they are at too low a frequency and are of too low and amplitude) and are not focussed upon the ischemic region.
As can be seen from the above, the prior art does not recite an acoustical method for inducing or assisting angiogenesis which reaches its vascular target with a high degree of efficiency.
A practical, low risk, non-invasive system to promote angiogenesis, and more particularly coronary angiogenesis via the use of high intensity mechanical reciprocating percussive force applied directly over, or proximate the ischemic region, such as to reach its target with highest efficiency is herein described.